The present invention is directed to xcex2-lactamase inhibitors useful in combination with xcex2-lactam antibiotics. More specifically, the present invention is directed to novel 3,6-disubstituted penam sulfone derivatives which demonstrate potent xcex2-lactamase inhibitory activity.
Penicillins and cephalosporins are the most frequently and widely used xcex2-lactam antibiotics. However, the development of bacterial resistance to these antibiotics has had a damaging effect on maintaining the effective treatment of bacterial infections.
The most significant, known mechanism related to the development of bacterial resistance to the xcex2-lactam antibiotics is the production of Class A and Class C serine xcex2-lactamases. These xcex2-lactamases compounds degrade the xcex2-lactam antibiotics, resulting in a loss of antibacterial activity. It is known that Class A serine xcex2-lactamases, which have molecular weights of about 29 kDa, preferentially hydrolyze penicillins, whereas Class C serine xcex2-lactamases which have molecular weights of about 39 kDa, preferentially hydrolyze cephalosporins. Bacterial resistance to these antibiotics could be greatly reduced by administering the xcex2-lactam antibiotic in combination with a compound which inhibits these enzymes.
A number of xcex2-lactamase inhibitors are known in the art. For example, U.S. Pat. No. 4,234,579 discloses penicillanic acid 1,1-dioxide (i.e., Sulbactam) useful for enhancing the activity of a number of xcex2-lactam antibiotics. U.S. Pat. No. 4,562,073 discloses a penicillin derivative (Tazobactam) useful as a xcex2-lactamase inhibitor. Likewise, U.S. Pat. Nos. 4,287,181 and 5,637,579 disclose penicillanic acid derivatives useful in enhancing the effectiveness of xcex2-lactam antibiotics. However, the compounds disclosed in these patents are active only towards Class A serine xcex2-lactamases and demonstrate poor activity against Class C serine xcex2-lactamases.
Two positions can be modified in the penam sulfone base structure: the 3 xcex2-methyl group and the 6-position. In the compounds discussed above, only one of the 3 or 6 positions is modified. Thus far, such a singular modification on the penam sulfone structure has not produced the desired activity against both Class A and Class C serine xcex2-lactamases. Accordingly, it can be seen that there is a need for compounds having such dual activities.
The present invention provides compounds having xcex2-lactamase inhibitory activity against both Class A and Class C serine xcex2-lactamases.
The present invention is directed to compounds of the following formulae I and II: 
wherein
n is 0 or 1 and
when n=1, R is a 5 or 6 membered heterocyclic ring, hydroxy, halogen, oxo, carbamoyl, alkoxy, disubstituted amino, or
when n=0, R is an ester, cyano or amide group;
X is CH or NH;
R3 is cyano, methoxy or acetamido; and
R1 is hydrogen, alkyl, a negative charge, a cation selected from the group consisting of sodium, potassium and tetraalkylammonium and acyloxyalkyl, or alkoxycarbonyloxyalkyl; and
R2 is hydrogen, acyl, trisubstituted silyl carbamoyl or an amino acid residue; or pharmaceutically acceptable salts thereof.